*Abhirama B SarepakaN 0241092

What is Alzheimers DiseaseIs the most common form of Dementia.Is incurable, terminal ailment affecting the brain mainly the Memory and Language centres (Areas 44-45 for language and the temporal lobe.)

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*Areas Affected and A Patient of Alzheimers

Pathophysiology of Alzheimers Disease*

Treatment of Alzheimers DiseaseNo permanent cure for Alzheimers disease.

The class of drugs used in the treatment of Alzheimers Disease are called Acetylcholinesterase (AChEs) Inhibitors.

These agents occur naturally in the form of venom and poisons e.g. Scorpion and Snake Venom; Belladonna.

Synthetically, they comprise of agents such as Organophosphates, Carbamates such as Rivastigmine, Phenantherene derivatives such as Galantamine and Piperidine derivatives such as Donepezil.*

*Donepezil: 2-[(1-benzyl-4-piperidyl)methyl]-5,6-dimethoxy-2,3 dihydroinden-1-oneGalantamine: (4aS, 6R, 8aS)-5, 6, 9, 10, 11, 12-hexahydro-3-methoxy-11-methyl-4aH-[1] benzofuro[3a, 3, 2-ef] [2] benzapin-6-olRivastigmine: (S)-N-Ethyl-N-methyl-3-[1-(dimethylamino) ethyl]-phenyl carbamate

Mechanism of interaction of Donepezil with Acetylcholinesterase*Minor grooveMajor grooveThe active site gorge has two binding sites, a catalytic site (consisting of the catalytic triad together with Trp84 & Phe330) and a peripheral site (including Trp 279 & Tyr 121), which helps prebind the substrate and direct it toward the active site.The X-ray structure of the Donepezil-TcAChE complex shows that Donepezil has unique orientation with active-site gorge.Donepezil does not, however, interact directly with either the catalytic triad or the 'oxyanion hole' but only indirectly via solvent molecules Bioavailability: 100% Half-life elimination: 70 hours; time to steady-state: 15 days Time to peak, plasma: 3-4 hours

Studies carried out on Donepezil*Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

Side effects of Donepezil Vs Placebo*Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

Mechanism of interaction of Galantamine with Acetylcholinesterase*The structure of the complex of GAL and TcAChE shows that GAL binds at the base of the gorge interacting with both the acyl-binding pocket and the principal quaternary ammonium-binding site, the indole ring of Trp-84.Absorption of galantamine is rapid and complete and shows linear pharmacokinetics.

It is well absorbed with absolute oral bioavailability between 80 and 100%. It has a half-life of 7 hours.Galantamine is a competitive and reversible cholinesterase inhibitor.

It is believed it works by enhancing cholinergic function by increasing the concentration of acetylcholine in the brain.

Studies on Rivastigmine and galantamine*Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

Side effects of Rivastigmine and Galantamine*Cholinesterase inhibitors for patients with Alzheimers Disease: Systematic review of randomised clinical trials BMJ 2005;331;321-327

Comparitive Analysis of Donepezil and GalantamineFrom the clinical trials, it is evident that Donepezil has a better effect as a Acetylcholinesterase Inhibitor as compared to Galantamine or Rivastigmine.

However, further research is still on to determine the extent of the beneficial nature of Donepezil as compared to Galantamine and Rivastigmine. *

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